The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

One Pass Thalamic and Subthalamic Stimulation for Patients with Tremor-Dominant Idiopathic Parkinson Syndrome (OPINION): Protocol for a Randomized, Active-Controlled, Double-Blinded Pilot Trial.

BACKGROUND: Besides fluctuations, therapy refractory tremor is one of the main indications of deep brain stimulation (DBS) in patients with idiopathic Parkinson syndrome (IPS). Although thalamic DBS (ventral intermediate nucleus [Vim] of thalamus) has been shown to reduce tremor in 85-95% of patients, bradykinesia and rigidity often are not well controlled. The dentato-rubro-thalamic tract (DRT) that can directly be targeted with special diffusion tensor magnetic resonance imaging sequences has been shown as an efficient target for thalamic DBS. The subthalamic nucleus (STN) is typically chosen in younger patients as the target for dopamine-responsive motor symptoms. This study investigates a one-path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and possibly a combined stimulation strategy for both target regions. OBJECTIVE: This study investigates a one path thalamic (Vim/DRT) and subthalamic implantation of DBS electrodes and a possibly combined stimulation strategy for both target regions. METHODS: This is a randomized, active-controlled, double-blinded (patient- and observer-blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design. Eighteen patients will undergo one-path thalamic (Vim/DRT) and STN implantation of DBS electrodes. After one month, a double-blinded and randomly-assigned stimulation of the thalamic target (Vim/DRT), the STN and a combined stimulation of both target regions will be performed for a period of three months each. The primary objective is to assess the quality of life obtained by the Parkinson's Disease Questionnaire (39 items) for each stimulation modality. Secondary objectives include tremor reduction (obtained by the Fahn-Tolosa-Marin tremor rating scale, video recordings, the Unified Parkinson's disease rating scale, and by tremor analysis), psychiatric assessment of patients, and to assess the safety of intervention. RESULTS: At the moment, the recruitment is stopped and 12 patients have been randomized and treated. A futility analysis is being carried out by means of a conditional power analysis. CONCLUSIONS: The approach of the OPINION trial planned to make, for the first time, a direct comparison of the different stimulation conditions (Vim/DRT, compared to STN, compared to Vim/DRT+STN) in a homogeneous patient population and, furthermore, will allow for intraindividual comparison of each condition with the "quality of life" outcome parameter. We hypothesize that the combined stimulation of the STN and the thalamic (Vim/DRT) target will be superior with respect to the patients' quality of life as compared to the singular stimulation of the individual target regions. If this holds true, this work might change the standardized treatment described in the previous section. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02288468; https://clinicaltrials.gov/ct2/show/NCT02288468 (Archived by WebCite at http://www.webcitation.org/6wlKnt2pJ); and German Clinical Trials Register: DRKS00007526; https://www.drks.de/drks_ web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007526 (Archived by WebCite at http://www.webcitation.org/6wlKyXZZL).

T2* Relaxometry in Patients with Parkinson's Disease : Use of an Automated Atlas-based Approach.

BACKGROUND: Magnetic resonance (MR) relaxometry is of increasing scientific relevance in neurodegenerative disorders but is still not established in clinical routine. Several studies have investigated relaxation time alterations in disease-specific areas in Parkinson's disease (PD), all using manually drawn regions of interest (ROI). Implementing MR relaxometry into the clinical setting involves the reduction of time needed for postprocessing using an investigator-independent and reliable approach. The aim of this study was to evaluate an automated, atlas-based ROI method for evaluating T2* relaxation times in patients with PD. METHOD: Automated atlas-based ROI analysis of quantitative T2* maps were generated from 20 PD patients and 20 controls. To test for the accuracy of the atlas-based ROI segmentation, we evaluated the spatial overlap in comparison with manually segmented ROIs using the Dice similarity coefficient (DSC). Additionally, we tested for group differences using our automated atlas-based ROIs of the putamen, globus pallidus, and substantia nigra. RESULTS: A good spatial overlap accuracy was shown for the automated segmented putamen (mean DSC, 0.64 ± 0.04) and was inferior but still acceptable for the substantia nigra (mean DSC, 0.50 ± 0.17). Based on our automated defined ROI selection, a significant decrease of T2* relaxation time was found in the putamen as well as in the internal and external globus pallidus in PD patients compared with healthy controls. CONCLUSION: Automated digital brain atlas-based approaches are reliable, more objective and time-efficient, and therefore have the potential to replace the time-consuming manual drawing of ROIs.

Reliability of the Infraspinatus Test in Carpal Tunnel Syndrome: A Clinical Study.

INTRODUCTION: Recently, a standardized provocation tests for the infraspinatus muscle, the Infraspinatus test (IsT), aimed at clinically confirming Carpal Tunnel Syndrome (CTS), was validated in a multiple-blind, controlled study. AIM: The present study was conducted to investigate inter-rater reliability of the IsT under conditions as they occur in daily clinical practice, since this is essential for acceptance of any new test. MATERIALS AND METHODS: Two raters from different medical disciplines used the IsT in the same group of subjects at different localities and with an interval of two to four weeks. Arms with symptoms of CTS were examined and compared with a control group of arms without symptoms. Nerve conduction studies were performed in all the subjects. Statistical analysis was performed with Cohen's Kappa (for inter-rater reliability) and McNemar's test (for determining dependencies between arms and raters). RESULTS: A total of 34 subjects (age 35-86 years) were investigated with the IsT by two raters in a blinded fashion. There was a high agreement between raters with a Kappa statistic of κ=0.868, when performing this new provocation test. The McNemar test did not reveal dependencies between Rater A and Rater B (p=0.6171), nor between the left and right arms of subjects (Rater A: p=0.4533, Rater B: p=0.5023). CONCLUSION: The new provocation test of the infraspinatus muscle is not only capable of confirming CTS, as was shown before, but is also a reliable method for use by different examiners under customary conditions.

Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult.

Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.

Manual MRI morphometry in Parkinsonian syndromes.

BACKGROUND: Several morphometric magnetic resonance imaging parameters may serve for differential diagnosis of parkinsonism. The objective of this study was to identify which performs best in clinical routine. METHODS: We acquired multicentric magnetization-prepared rapid gradient echo sequences in patients with Parkinson's disease (n=204), progressive supranuclear palsy (n=106), multiple system atrophy-cerebellar, (n = 21); multiple system atrophy-parkinsonian (n = 60), and healthy controls (n = 73), performed manual planimetric measurements, and calculated receiver operator characteristics with leave-one-out cross-validation to propose cutoff values. RESULTS: The midsagittal midbrain area was reduced in PSP versus all other groups (P < 0.001). The midsagittal pons area was reduced in MSA-cerebellar, MSA-parkinsonian, and PSP versus PD patients and healthy controls (P < 0.001). The midbrain/pons area ratio was lower in PSP (P < 0.001) and higher in MSA-cerebellar and MSA-parkinsonian versus PD and PSP (P < 0.001). CONCLUSIONS: The midsagittal midbrain area most reliably identified PSP, the midsagittal pons area MSA-cerebellar. The midbrain/pons area ratio differentiated MSA-cerebellar and PSP better than the magnetic resonance-Parkinson index. © 2017 International Parkinson and Movement Disorder Society.

Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): Study Protocol of a Randomized Controlled Feasibility Trial.

BACKGROUND: Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim-DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used. OBJECTIVE: This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient. METHODS: The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg. RESULTS: Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment. CONCLUSIONS: The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery. CLINICALTRIAL: ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS).

Differentiation of neurodegenerative parkinsonian syndromes by volumetric magnetic resonance imaging analysis and support vector machine classification.

BACKGROUND: Clinical differentiation of parkinsonian syndromes is still challenging. OBJECTIVES: A fully automated method for quantitative MRI analysis using atlas-based volumetry combined with support vector machine classification was evaluated for differentiation of parkinsonian syndromes in a multicenter study. METHODS: Atlas-based volumetry was performed on MRI data of healthy controls (n = 73) and patients with PD (204), PSP with Richardson's syndrome phenotype (106), MSA of the cerebellar type (21), and MSA of the Parkinsonian type (60), acquired on different scanners. Volumetric results were used as input for support vector machine classification of single subjects with leave-one-out cross-validation. RESULTS: The largest atrophy compared to controls was found for PSP with Richardson's syndrome phenotype patients in midbrain (-15%), midsagittal midbrain tegmentum plane (-20%), and superior cerebellar peduncles (-13%), for MSA of the cerebellar type in pons (-33%), cerebellum (-23%), and middle cerebellar peduncles (-36%), and for MSA of the parkinsonian type in the putamen (-23%). The majority of binary support vector machine classifications between the groups resulted in balanced accuracies of >80%. With MSA of the cerebellar and parkinsonian type combined in one group, support vector machine classification of PD, PSP and MSA achieved sensitivities of 79% to 87% and specificities of 87% to 96%. Extraction of weighting factors confirmed that midbrain, basal ganglia, and cerebellar peduncles had the largest relevance for classification. CONCLUSIONS: Brain volumetry combined with support vector machine classification allowed for reliable automated differentiation of parkinsonian syndromes on single-patient level even for MRI acquired on different scanners. © 2016 International Parkinson and Movement Disorder Society.

One-pass deep brain stimulation of dentato-rubro-thalamic tract and subthalamic nucleus for tremor-dominant or equivalent type Parkinson's disease.

BACKGROUND: Refractory tremor in tremor-dominant (TD) or equivalent-type (EQT) idiopathic Parkinson's syndrome (IPS) poses the challenge of choosing the best target region to for deep brain stimulation (DBS). While the subthalamic nucleus is typically chosen in younger patients as the target for dopamine-responsive motor symptoms, it is more complicated if tremor does not (fully) respond under trial conditions. In this report, we present the first results from simultaneous bilateral DBS of the DRT (dentato-rubro-thalamic tract) and the subthalamic nucleus (STN) in two elderly patients with EQT and TD IPS and dopamine-refractory tremor. METHODS: Two patients received bilateral octopolar DBS electrodes in the STN additionally traversing the DRT region. Achieved electrode positions were determined with helical CT, overlaid onto DTI tractography data, and compared with clinical data of stimulation response. RESULTS: Both patients showed immediate and sustained improvement of their tremor, bilaterally. CONCLUSIONS: The proposed approach appears to be safe and feasible and a combined stimulation of the two target regions was performed tailored to the patients' symptoms. Clinically, no neuropsychiatric effects were seen. Our pilot data suggest a viable therapeutic option to treat the subgroup of TD and EQT IPS and with tremor as the predominant symptom. A clinical study to further investigate this approach ( OPINION: www.clinicaltrials.gov ; NCT02288468) is the focus of our ongoing research.

Deep Brain Stimulation in Neurological and Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is the chronic electrical stimulation of selected target sites in the brain through stereotactically implanted electrodes. More than 150 000 patients around the world have been treated to date with DBS for medically intractable conditions. The indications for DBS include movement disorders, epilepsy, and some types of mental illness. METHODS: This review is based on relevant publications retrieved by a selective search in PubMed and the Cochrane Library, and on the current guidelines of the German Neurological Society (Deutsche Gesellschaft für Neurologie, DGN). RESULTS: DBS is usually performed to treat neurological diseases, most often movement disorders and, in particular, Parkinson's disease. Multiple randomized controlled trials (RCTs) have shown that DBS improves tremor, dyskinesia, and quality of life in patients with Parkinson's disease by 25% to 50%, depending on the rating scales used. DBS for tremor usually involves stimulation in the cerebello-thalamo-cortical regulatory loop. In an RCT of DBS for the treatment of primary generalized dystonia, the patients who underwent DBS experienced a 39.3% improvement of dystonia, compared to only 4.9% in the control group. Two multicenter trials of DBS for depression were terminated early because of a lack of efficacy. CONCLUSION: DBS is an established treatment for various neurological and psychiatric diseases. It has been incorporated in the DGN guidelines and is now considered a standard treatment for advanced Parkinson's disease. The safety and efficacy of DBS can be expected to improve with the application of new technical developments in electrode geometry and new imaging techniques. Controlled trials would be helpful so that DBS could be extended to further indications, particularly psychiatric ones.

18F-FDG PET Is an Early Predictor of Overall Survival in Suspected Atypical Parkinsonism.

UNLABELLED: Early prognostic stratification is desirable in patients with suspected atypical parkinsonian syndromes (APSs) for optimal treatment and counseling. We investigated the prognostic value of imaging disease-specific metabolism patterns with 18F-FDG PET compared with that of clinical diagnosis. METHODS: Seventy-eight patients with suspected APS at study inclusion underwent a follow-up of up to 5.9 y after prospective 18F-FDG PET imaging. Survival data were analyzed by Kaplan-Meier and Cox regression analyses according to diagnostic classifications provided by 18F-FDG PET at baseline and clinical diagnoses after a median follow-up of 1 y after PET. RESULTS: Forty-four of 78 patients were alive 4.7±0.6 y after PET. Patients diagnosed with an APS by PET or 1-y clinical follow-up showed a significantly shorter median survival time (4.1 y, age-adjusted hazard ratios [HRs]=3.8 for both classifiers) than those diagnosed with Lewy-body diseases (LBDs; majority Parkinson disease [PD]; median survival time not reached). Subgroup classifications of progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) or multiple-system atrophy (MSA) by PET and clinical follow-up were associated with significantly shorter survival than PD. Age-adjusted mortality was significantly increased for PSP/CBD (HR=5.2) and MSA (HR=5.6) classified by PET, but for PSP/CBD only when diagnosed by clinical follow-up (HR=4.5). Patients with a PET pattern suggestive of PD with dementia/dementia with Lewy bodies (PDD/DLB) exhibited a trend toward shorter survival than those with PD (P=0.07), whereas patients classified as PDD/DLB by clinical follow-up did not (P=0.65). CONCLUSION: 18F-FDG PET is an early predictor of survival in patients with clinically suspected APS. Detection of cortical or subcortical hypometabolism by 18F-FDG PET is an unfavorable predictor. Risk stratification by 18F-FDG PET appears to be at least as predictive as the 1-y follow-up clinical diagnosis. This finding strongly supports the early inclusion of PET imaging in patient care.

Assessment of planning performance in clinical samples: Reliability and validity of the Tower of London task (TOL-F).

OBJECTIVE: Executive deficits are frequent sequelae of neurological and psychiatric disorders, but their adequate neuropsychological assessment is still a matter of contention, given that executive tasks draw on a multitude of cognitive processes that are often not sufficiently specified. In line with this, results on psychometric properties of the Tower of London, a task measuring planning ability as a prototypical executive function, are equivocal and furthermore lacking completely for adult clinical populations. METHODS: We used a structurally balanced item set implemented in the Tower of London (Freiburg version, TOL-F) that accounts for major determinants of problem difficulty beyond the commonly used minimum number of moves to solution. Split-half reliability, internal consistency, and criterion-related concurrent validity of TOL-F accuracy were assessed in patients with stroke (N = 60), Parkinson syndrome (N = 51), and mild cognitive impairment (N = 29), and healthy adults (N = 155). RESULTS: Across samples, mean split-half and lower-bound indices of reliability of accuracy scores were adequate (r ≥ .7) or higher. Compared to a subset of healthy controls matched for age, sex, and education levels, deficits in planning accuracy emerged for all three clinical samples. CONCLUSIONS: Based on consistently adequate reliability and a good criterion-related validity of accuracy scores, the TOL-F demonstrates its utility for testing planning ability in clinical samples and healthy adults. Using item sets systematically accounting for several determinants of task difficulty can thus significantly enhance the contended reliability of executive tasks and provide an opportunity to resolve the underspecification of cognitive processes contributing to executive functioning in health and disease.

Role of semiquantitative assessment of regional binding potential in 123I-FP-CIT SPECT for the differentiation of frontotemporal dementia, dementia with Lewy bodies, and Alzheimer's dementia.

INTRODUCTION: I-FP-CIT SPECT is increasingly used to differentiate between Alzheimer's dementia (AD) and dementia with Lewy bodies (DLB). The role of I-FP-CIT SPECT in frontotemporal dementia (FTD) is rather unclear, albeit nigrostriatal involvement may occur. The aim of this study was to evaluate its role in the differentiation of FTD, DLB, and AD. METHODS: We analyzed 34 patients with clinical diagnosis of FTD (n = 13), DLB (n = 12), and AD (n = 9) undergoing combined F-FDG PET and I-FP-CIT SPECT. We performed a semiquantitative region of interest-based analysis to determine the binding potential values in caudate nucleus, putamen, and whole striatum including the caudate/putamen binding potential ratio and asymmetry indices. The receiver operating characteristic analyses and multinomial logistic regression were conducted to assess discrimination accuracy. RESULTS: The putaminal binding potential separated DLB from AD with high accuracy (area under the receiver operating characteristic curve [AUC], 0.94). It also discriminated FTD from DLB with high accuracy (AUC, 0.92), whereas differentiation between FTD and AD was less accurate (AUC, 0.74). The binding potential ratio also provided high accuracy for differentiation of FTD and DLB (AUC, 0.91). Combination of these 2 parameters yielded slightly higher results for differentiation of FTD and DLB (AUC, 0.97). In a group including all patients, accuracy remained very high for DLB (AUC, 0.95), whereas values for FTD (AUC, 0.81) and AD (AUC, 0.80) were lower. CONCLUSIONS: Semiquantitative assessment of striatal dopamine transporter availability can differentiate between FTD and DLB as well as DLB and AD with high accuracy, whereas discrimination between AD and FTD is limited.

Syndrome-specific patterns of regional cerebral glucose metabolism in posterior cortical atrophy in comparison to dementia with Lewy bodies and Alzheimer's disease--a [F-18]-FDG pet study.

BACKGROUND: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome with visuospatial deficits. PET studies have identified hypometabolism of the occipital cortex in PCA. There is, however, a huge overlap in clinical presentation and involvement of the occipital cortex between PCA, dementia with Lewy bodies (DLB), and Alzheimer's disease (AD). Syndrome-specific patterns of metabolism have not yet been demonstrated that allow for a reliable differentiation with [F-18]-FDG-PET. METHODS: A total of 33 dementia patients (PCA n = 6, DLB n = 12, AD n = 15) who underwent [F-18]-FDG-PET imaging and a neuropsychological examination were retrospectively analyzed. Group comparisons of regional cerebral glucose metabolism were calculated with statistical parametric mapping. Extracted clusters were used to evaluate discrimination accuracy by logistic regression. RESULTS: PCA patients showed a syndrome-specific area of hypometabolism in the right lateral temporooccipital cortex. DLB patients showed specific hypometabolism predominantly in the left occipital cortex. Logistic regression based on these two regions correctly separated patients with a sensitivity/specificity of 83/93% for PCA, 75/86% for DLB and 67/78% for AD. Overall accuracy was 73%. CONCLUSION: [F-18]-FDG-PET could reveal syndrome-specific patterns of glucose metabolism in PCA and DLB. Accurate group discrimination in the differential diagnosis of dementia with visuospatial impairment is feasible.

Suppression of enhanced physiological tremor via stochastic noise: initial observations.

Enhanced physiological tremor is a disabling condition that arises because of unstable interactions between central tremor generators and the biomechanics of the spinal stretch reflex. Previous work has shown that peripheral input may push the tremor-related spinal and cortical systems closer to anti-phase firing, potentially leading to a reduction in tremor through phase cancellation. The aim of the present study was to investigate whether peripherally applied mechanical stochastic noise can attenuate enhanced physiological tremor and improve motor performance. Eight subjects with enhanced physiological tremor performed a visuomotor task requiring the right index finger to compensate a static force generated by a manipulandum to which Gaussian noise (3-35 Hz) was applied. The finger position was displayed on-line on a monitor as a small white dot which the subjects had to maintain in the center of a larger green circle. Electromyogram (EMG) from the active hand muscles and finger position were recorded. Performance was measured by the mean absolute deviation of the white dot from the zero position. Tremor was identified by the acceleration in the frequency range 7-12 Hz. Two different conditions were compared: with and without superimposed noise at optimal amplitude (determined at the beginning of the experiment). The application of optimum noise reduced tremor (accelerometric amplitude and EMG activity) and improved the motor performance (reduced mean absolute deviation from zero). These data provide the first evidence of a significant reduction of enhanced physiological tremor in the human sensorimotor system due to application of external stochastic noise.

A disease-specific metabolic brain network associated with corticobasal degeneration.

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.

Estrogen intake and copper depositions: implications for Alzheimer's disease?

We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.

Functional correlates of vertical gaze palsy and other ocular motor deficits in PSP: an FDG-PET study.

OBJECTIVE: To determine the functional correlates of vertical gaze palsy and other ocular motor deficits in patients with progressive supranuclear palsy (PSP) using [(18)F]fluorodeoxyglucose (FDG-)PET. METHODS: Twenty-six patients with PSP underwent clinical examination of vertical gaze combined with FDG-PET scans to assess regional cerebral glucose metabolism as a marker of neuronal activity. Of these, eighteen PSP patients were also investigated by electrical nystagmography to determine horizontal ocular motor deficits. Statistical parametric mapping analyses were performed to correlate regional neuronal activity with ocular motor functions. RESULTS: In categorical comparisons, patients with downward gaze palsy showed a significantly reduced glucose metabolism in bilateral anterior cingulate gyrus and right lingual gyrus compared to those without downward gaze palsy. Maximum velocity of horizontal saccades was positively correlated with glucose metabolism of the rostral vermis and lingual gyrus; regional metabolism of oculomotor vermis was associated with peak velocity of the optokinetic reflex. Analysis of smooth pursuit eye movement amplitude and peak velocity of corrective saccades showed positive correlation with metabolism in bilateral inferior parietal lobe and inferior part of the frontal eye field. All paradigms of smooth pursuit showed positive association with glucose metabolism in V5. CONCLUSIONS: Ocular motor functions in PSP are correlated with neuronal activity in distinct anatomical regions. These include the anterior cingulate gyrus (downward gaze palsy), rostral cerebellum (saccades), oculomotor vermis (optokinetic reflex) and inferior parietal as well as temporal regions and frontal eye field (smooth pursuit). These findings provide a deeper insight into the pathophysiology of PSP-associated ocular motor abnormalities.

Neuronal correlates of clinical asymmetry in progressive supranuclear palsy.

PURPOSE: Progressive supranuclear palsy (PSP) is characterized by a symmetric hypokinetic syndrome with early falls and vertical supranuclear gaze palsy. However, clinically asymmetric manifestations occur, resembling idiopathic Parkinson disease or corticobasal degeneration. The aim of this study was to determine the neuronal correlates of patients suffering from PSP with a lateralized disease manifestation (hemi-PSP) in comparison to patients with symmetric clinical presentation (symPSP) and corticobasal degeneration. METHODS: Twenty-three patients with PSP and 8 patients with corticobasal degeneration according to standard diagnostic criteria underwent F-fluorodeoxyglucose (FDG) PET scans to assess disease-specific patterns of regional cerebral glucose metabolism reflecting neuronal activity. Group differences were analyzed by statistical parametric mapping and region-of-interest analyses. RESULTS: Clinically, 14 patients presented with symPSP while 9 patients were considered as hemi-PSP. Patients with symPSP or hemi-PSP showed similar bilateral medial frontal hypometabolism compared to corticobasal degeneration patients. In contrast, corticobasal degeneration patients exhibited a prominent parietal hypometabolism compared to both symPSP and hemi-PSP patients. SymPSP patients showed no significant hypometabolism compared to hemi-PSP, whereas hemi-PSP patients presented with significant hypometabolism of the motor thalamus, middle cingulate gyrus, and sensorimotor cortex contralateral to the most affected body side compared to symPSP patients. CONCLUSIONS: The present study demonstrates that a more pronounced and asymmetric involvement of cortical and subcortical motor areas is associated with a lateralized disease manifestation of PSP. Furthermore, these findings strongly suggest that FDG PET imaging may assist the challenging clinical differentiation between hemi-PSP and corticobasal degeneration by depicting disease-specific patterns of regional cerebral glucose metabolism.

Hypokinesia upon Pallidal Deep Brain Stimulation of Dystonia: Support of a GABAergic Mechanism.

In the past, many studies have documented the beneficial effects of deep brain stimulation (DBS) in the globus pallidus internus for treatment of primary segmental or generalized dystonia. Recently however, several reports focused on DBS-induced hypokinesia or freezing of gait (FOG) as a side effect in these patients. Here we report on two patients suffering from FOG after successful treatment of their dystonic movement disorder with pallidal high frequency stimulation (HFS). Several attempts to reduce the FOG resulted in worsening of the control of dystonia. In one patient levodopa treatment was initialized which was somewhat successful to relieve FOG. We discuss the possible mechanisms of hypokinetic side effects of pallidal DBS which can be explained by the hypothesis of selective GABA release as the mode of action of HFS. Pallidal HFS is also effective in treating idiopathic Parkinson's disease as a hypokinetic disorder which at first sight seems to be a paradox. In our view, however, the GABAergic hypothesis can explain this and other clinical observations.